The Imidazopyridine Derivative JK184 Reveals Dual Roles for Microtubules in Hedgehog Signaling

Cupido, Tommaso; Rack, Philip D.; Firestone, Ari J.; Hyman, Joel M.; Han, Ke; Sinha, Surajit; Ocasio, Cory A.; Chen, James

doi:10.1002/anie.200805666

Cited by 37 publications

(13 citation statements)

References 24 publications

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“…Hedgehog response was assayed using an NIH3T3 reporter cell line that expresses GFP under the control of Gli response elements [13], [14]. NIH3T3::Gli-GFP cells were transfected with Plk4 to generate super-ciliated cells and treated with Shh, inducing expression of Gli-GFP.…”

Section: Resultsmentioning

confidence: 99%

Supernumerary Centrosomes Nucleate Extra Cilia and Compromise Primary Cilium Signaling

2012

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Summary The primary cilium is a nexus of cell signaling, and ciliary dysfunction is associated with polycystic kidney disease, retinal degeneration, polydactyly, neural tube defects, and obesity (ciliopathies) [1]. Signaling molecules for cilium-associated pathways are concentrated in the cilium, and this is essential for efficient signaling. Cilia are nucleated from centrioles, and aberrant centriole numbers are seen in many cancers and in some ciliopathies [2]. We tested the effect of supernumerary centrioles on cilium function, and found that cells with extra centrioles often formed more than one cilium, had reduced ciliary concentration of Smoothened in response to Sonic hedgehog stimulation, and reduced Shh pathway transcriptional activation. This ciliary dilution phenotype was also observed with the serotonin receptor Htr6, fibrocystin PKHD1, and Arl13b. The presence of extra centrioles and cilia disrupted epithelial organization in 3-D spheroid culture. Cells mutant for the tuberous sclerosis gene Tsc2 also had extra cilia and diluted ciliary protein. In most cells extra cilia were clustered and shared the same ciliary pocket, suggesting that the ciliary pocket is the rate-limiting structure for trafficking of ciliary proteins. Thus, extra centrioles and cilia disrupt signaling, and may contribute to disease phenotypes.

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Section: Resultsmentioning

confidence: 99%

Supernumerary Centrosomes Nucleate Extra Cilia and Compromise Primary Cilium Signaling

2012

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“…Such an interaction with the zinc fingers of Gli proteins could affect their normal structure, thus disrupting their interaction with other proteins or DNA. Alternatively, arsenicals are known to interact with tubulin, and this interaction could antagonize Hh response (8,58,59) and affect the ability of Gli proteins to traffic to the cilium without perturbing Smo trafficking to the cilium (8). With longer-term treatment, arsenic causes a reduction in the levels of Gli2, and this effect also could be mediated by disruption of structure of Gli, leading to proteasomal degradation.…”

Section: Discussionmentioning

confidence: 99%

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

Kim

Lee

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

285

244

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Aberrant Hedgehog (Hh) pathway activation has been implicated in cancers of diverse tissues and organs, and the tumor growth-inhibiting effects of pathway antagonists in animal models have stimulated efforts to develop pathway antagonists for human therapeutic purposes. These efforts have focused largely on cyclopamine derivatives or other compounds that mimic cyclopamine action in binding to and antagonizing Smoothened, a membrane transductory component. We report here that arsenicals, in contrast, antagonize the Hh pathway by targeting Gli transcriptional effectors; in the short term, arsenic blocks Hh-induced ciliary accumulation of Gli2, the primary activator of Hh-dependent transcription, and with prolonged incubation arsenic reduces steady-state levels of Gli2. Arsenicals active in Hh pathway antagonism include arsenic trioxide (ATO), a curative agent in clinical use for acute promyelocytic leukemia (APL); in our studies, ATO inhibited growth of Hh pathway-driven medulloblastoma allografts derived from Ptch +/− p53 −/− mice within a range of serum levels comparable to those achieved in treatment of human APL. Arsenic thus could be tested rapidly as a therapeutic agent in malignant diseases associated with Hh pathway activation and could be particularly useful in such diseases that are inherently resistant or have acquired resistance to cyclopamine mimics.

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“…Shh-EGFP (17,18) and Shh-LIGHT2 cells (46) have been described. Smo −/− MEFs were provided by P. Beachy (Stanford University, Stanford, CA), and Sufu −/− MEFs were provided by R. Toftgård (Karolinska Institute, Stockholm).…”

Section: Methodsmentioning

confidence: 99%

“…cell-derived line stably transfected with a Gli-dependent enhanced green fluorescent protein reporter (Shh-EGFP cells) (17,18), retroviral pools encoding sublibraries of the ORF collection, and a fluorescence-activated cell sorting (FACS)-based assay for ascertaining Hh pathway activity in single cells (Fig. 1A and SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

Arhgap36-dependent activation of Gli transcription factors

Rack¹,

Ni²,

Payumo³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are upregulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.

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The Imidazopyridine Derivative JK184 Reveals Dual Roles for Microtubules in Hedgehog Signaling

Cited by 37 publications

References 24 publications

Supernumerary Centrosomes Nucleate Extra Cilia and Compromise Primary Cilium Signaling

Supernumerary Centrosomes Nucleate Extra Cilia and Compromise Primary Cilium Signaling

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

Arhgap36-dependent activation of Gli transcription factors

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